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author:("currin, Lyle")
1.  Meta-analysis of incidence rate data in the presence of zero events 
When summary results from studies of counts of events in time contain zeros, the study-specific incidence rate ratio (IRR) and its standard error cannot be calculated because the log of zero is undefined. This poses problems for the widely used inverse-variance method that weights the study-specific IRRs to generate a pooled estimate.
We conducted a simulation study to compare the inverse-variance method of conducting a meta-analysis (with and without the continuity correction) with alternative methods based on either Poisson regression with fixed interventions effects or Poisson regression with random intervention effects. We manipulated the percentage of zeros in the intervention group (from no zeros to approximately 80 percent zeros), the levels of baseline variability and heterogeneity in the intervention effect, and the number of studies that comprise each meta-analysis. We applied these methods to an example from our own work in suicide prevention and to a recent meta-analysis of the effectiveness of condoms in preventing HIV transmission.
As the percentage of zeros in the data increased, the inverse-variance method of pooling data shows increased bias and reduced coverage. Estimates from Poisson regression with fixed interventions effects also display evidence of bias and poor coverage, due to their inability to account for heterogeneity. Pooled IRRs from Poisson regression with random intervention effects were unaffected by the percentage of zeros in the data or the amount of heterogeneity.
Inverse-variance methods perform poorly when the data contains zeros in either the control or intervention arms. Methods based on Poisson regression with random effect terms for the variance components are very flexible offer substantial improvement.
Electronic supplementary material
The online version of this article (doi:10.1186/s12874-015-0031-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4422043  PMID: 25925169
Meta-analysis; Person-time; Incidence rate ratio; Sparse data
2.  Overview of methods for comparing the efficacies of drugs in the absence of head-to-head clinical trial data 
In most therapeutic areas, multiple drug options are increasingly becoming available, but there is often a lack of evidence from head-to-head clinical trials that allows for direct comparison of the efficacy and/or safety of one drug vs. another. This review provides an introduction to, and overview of, common methods used for comparing drugs in the absence of head-to-head clinical trial evidence. Naïve direct comparisons are in most instances inappropriate and should only be used for exploratory purposes and when no other options are possible. Adjusted indirect comparisons are currently the most commonly accepted method and use links through one or more common comparators. Mixed treatment comparisons (MTCs) use Bayesian statistical models to incorporate all available data for a drug, even data that are not relevant to the comparator drug. MTCs reduce uncertainty but have not yet been widely accepted by researchers, nor drug regulatory and reimbursement authorities. All indirect analyses are based on the same underlying assumption as meta-analyses, namely that the study populations in the trials being compared are similar.
PMCID: PMC3895352  PMID: 23617453
adjusted indirect comparison; mixed treatment comparison; naïve direct comparison
3.  Metachronous colorectal cancer risk for mismatch repair gene mutation carriers – the advantage of more extensive colon surgery 
Gut  2010;60(7):10.1136/gut.2010.228056.
Surgical management of colon cancer for patients with Lynch Syndrome who carry a mismatch repair gene mutation is controversial. The decision to remove more or less of the colon involves the consideration of a relatively high risk of metachronous colorectal cancer (CRC) with the impact of more extensive surgery. Our aim was to estimate and compare the risks of metachronous CRC for Lynch Syndrome patients undergoing either segmental or extensive (subtotal or total) resection for first colon cancer.
Risk of metachronous CRC was estimated for 382 MMR gene mutation carriers (172 MLH1, 167 MSH2, 23 MSH6 and 20 PMS2) from the Colon Cancer Family Registry, who had surgery for their first colon cancer using retrospective cohort analysis. Age-dependent cumulative risks of metachronous CRC were calculated using the Kaplan-Meier method. Risk factors for metachronous CRC were assessed by a Cox proportional hazards regression.
None of 50 subjects who had extensive colectomy was diagnosed with metachronous CRC (incidence rate 0.0; 95%CI 0.0–7.2 per 1000 person-years). Of 332 subjects who had segmental resections, 74 (22%) were diagnosed with metachronous CRC (incidence rate 23.6; 95%CI 18.8–29.7 per 1000 person-years). For those who had segmental resections, incidence was statistically higher than for those who had extensive surgery (P <0.001). Cumulative risk of metachronous CRC was 16% (95%CI 10–25%) at 10 years, 41% (95%CI 30–52%) at 20 years and 62% (95%CI 50–77%) at 30 years after segmental colectomy. Risk of metachronous CRC reduced by 31% (95%CI 12–46%; P 0.002) for every 10 cm of bowel removed.
Lynch Syndrome patients with first colon cancer treated with more extensive colonic resection have a lower risk of metachronous CRC compared with those receiving less extensive surgery. This finding will better inform decision-making regarding the extent of primary surgical resection.
PMCID: PMC3848416  PMID: 21193451
Lynch Syndrome; metachronous colorectal cancer; colorectal surgery
4.  HFE C282Y homozygotes are at increased risk of breast and colorectal cancer 
Hepatology (Baltimore, Md.)  2010;51(4):10.1002/hep.23448.
The evidence that mutations in the HFE gene are associated with increased cancer risk is inconsistent.
The Melbourne Collaborative Cohort Study is a prospective cohort study that commenced recruitment in 1990. Participants of born in Australia, New Zealand, the United Kingdom or Ireland (n = 28,509) were genotyped for the HFE C282Y variant. Incident cancers were ascertained from Australian cancer registries during an average of 14 years follow up. Hazard ratios, confidence intervals and p-values were obtained from separate Cox regression analyses for colorectal, breast and prostate cancers, all other solid cancers and all cancers.
Compared with those with no C282Y variant, C282Y homozygotes were at increased risk of colorectal cancer (HR 2·28; 95% CI 1·22, 4·25; p = 0.01) and female C282Y homozygotes were at increased risk of developing breast cancer (HR 2·39; 95% CI 1·24, 4·61; p = 0.01) but male C282Y homozygotes were not at increased risk for prostate cancer (HR 0·96; 95% CI 0·43, 2·15; p = 0.92). C282Y/H63D compound heterozygotes were not at increased risk for colorectal cancer, (HR 1 27; 95% CI 0·80, 2·01); breast cancer, (HR 1·16; 95% CI 0·74, 1·84); or prostate cancer (HR 1·08; 95% CI 0·68, 1·70).
HFE C282Y homozygotes have twice the risk of colorectal and breast cancer compared with those without the C282Y variant.
PMCID: PMC3815603  PMID: 20099304
Haemochromatosis; neoplasm; prospective cohort; iron
5.  The Impact of Family History of Allergy on Risk of Food Allergy: A Population-Based Study of Infants 
The apparent rapid increase in IgE-mediated food allergy and its implications are now widely recognized, but little is known about the relationship between family history (an indirect measure of genetic risk) and the risk of food allergy. In a population-based study of 5,276 one year old infants (HealthNuts), the prevalence of oral food challenge-confirmed food allergy was measured. Associations between family history of allergic disease and food allergy in infants were examined using multiple logistic regression. Food allergy was diagnosed in 534 infants. Compared to those with no family history of allergic disease, children meeting the current definition of “high risk” for allergic disease (one immediate family member with a history of any allergic disease) showed only a modest increase (OR 1.4, 95% CI 1.1–1.7) in food allergy, while having two or more allergic family members was more strongly predictive of food allergy in the child (OR 1.8, 95% CI 1.5–2.3). There were also differences in the associations between family history and egg and peanut allergy in the child. Re-defining “high risk” as two or more allergic family members may be more useful for identification of groups with a significantly increased risk of food allergy both clinically and within research studies.
PMCID: PMC3863850  PMID: 24284354
food allergy; family history; genetics; heritability; siblings; maternal; paternal; egg allergy; peanut allergy
6.  The Natural History of IgE-Mediated Food Allergy: Can Skin Prick Tests and Serum-Specific IgE Predict the Resolution of Food Allergy? 
IgE-mediated food allergy is a transient condition for some children, however there are few indices to predict when and in whom food allergy will resolve. Skin prick test (SPT) and serum-specific IgE levels (sIgE) are usually monitored in the management of food allergy and are used to predict the development of tolerance or persistence of food allergy. The aim of this article is to review the published literature that investigated the predictive value of SPT and sIgE in development of tolerance in children with a previous diagnosis of peanut, egg and milk allergy. A systematic search identified twenty-six studies, of which most reported SPT or sIgE thresholds which predicted persistent or resolved allergy. However, results were inconsistent between studies. Previous research was hampered by several limitations including the absence of gold standard test to diagnose food allergy or tolerance, biased samples in retrospective audits and lack of systematic protocols for triggering re-challenges. There is a need for population-based, prospective studies that use the gold standard oral food challenge (OFC) to diagnose food allergy at baseline and follow-up to develop SPT and sIgE thresholds that predict the course of food allergy.
PMCID: PMC3823325  PMID: 24132133
food allergy; natural history; tolerance; skin prick test; serum-specific immunoglobulin E; hen’s egg; peanut; cow’s milk
7.  Peanut Allergen Threshold Study (PATS): validation of eliciting doses using a novel single-dose challenge protocol 
The eliciting dose (ED) for a peanut allergic reaction in 5% of the peanut allergic population, the ED05, is 1.5 mg of peanut protein. This ED05 was derived from oral food challenges (OFC) that use graded, incremental doses administered at fixed time intervals. Individual patients’ threshold doses were used to generate population dose-distribution curves using probability distributions from which the ED05 was then determined. It is important to clinically validate that this dose is predictive of the allergenic response in a further unselected group of peanut-allergic individuals.
This is a multi-centre study involving three national level referral and teaching centres. (Cork University Hospital, Ireland, Royal Children’s Hospital Melbourne, Australia and Massachusetts General Hospital, Boston, U.S.A.) The study is now in process and will continue to run until all centres have recruited 125 participates in each respective centre.
A total of 375 participants, aged 1–18 years will be recruited during routine Allergy appointments in the centres. The aim is to assess the precision of the predicted ED05 using a single dose (6 mg peanut = 1.5 mg of peanut protein) in the form of a cookie. Validated Food Allergy related Quality of Life Questionnaires-(FAQLQ) will be self-administered prior to OFC and 1 month after challenge to assess the impact of a single dose OFC on FAQL. Serological and cell based in vitro studies will be performed.
The validation of the ED05 threshold for allergic reactions in peanut allergic subjects has potential value for public health measures. The single dose OFC, based upon the statistical dose-distribution analysis of past challenge trials, promises an efficient approach to identify the most highly sensitive patients within any given food-allergic population.
PMCID: PMC3850217  PMID: 24028324
Eliciting dose (ED); Food Allergy related Quality of Life Questionnaires-(FAQLQ); Single dose; Peanut thresholds; Oral Food Challenges (OFC); Voluntary Incidental Trace Allergen Labelling (VITAL); Peanut Allergen Threshold Study (PATS)
8.  HFE C282Y/H63D Compound Heterozygotes Are at Low Risk of Hemochromatosis-Related Morbidity 
Hepatology (Baltimore, Md.)  2009;50(1):94-101.
The risk of hemochromatosis-related morbidity is unknown among HFE compound heterozygotes (C282Y/H63D). We used a prospective population-based cohort study to estimate the prevalence of elevated iron indices and hemochromatosis-related morbidity for compound heterozygotes. In all, 31,192 subjects of northern European descent were genotyped for HFE C282Y and H63D. An HFE-genotype stratified random sample of 1,438 subjects, followed for an average of 12 years to a mean age of 65 years, completed questionnaires and gave blood. Clinical examinations were blinded to HFE genotype. A total of 180 (84 males) clinically examined C282Y/H63D participants were compared with 330 (149 males) controls with neither HFE mutation; 132 (65 males) and 270 (122 males), respectively, had serum iron measures at both timepoints. Mean serum ferritin (SF) and transferrin saturation (TS) were significantly greater for male and female compound heterozygotes than for wild-types at baseline and follow-up (all P < 0.02) except for females who were pre-menopausal at baseline, where SF was similar in both genotype groups. For subjects with serum measures from both baseline and follow-up, mean SF and TS levels did not change significantly for men or for postmenopausal women, but for premenopausal women SF levels increased from 43 to 109 μg/L for compound heterozygotes and from 35 to 64 μg/L for wild-types (both P < 0.001). Male and female compound heterozygotes had a similar prevalence of hemochromatosis-related morbidity to wild-types. One of 82 males and zero of 95 females had documented iron overload-related disease.
For male compound heterozygotes, mean iron indices do not change during middle age but for female compound heterozygotes menopause results in increased mean SF. Although compound heterozygotes might maintain elevated iron indices during middle age, documented iron overload-related disease is rare.
PMCID: PMC3763940  PMID: 19554541
9.  Identification of doctors at risk of recurrent complaints: a national study of healthcare complaints in Australia 
BMJ quality & safety  2013;22(7):532-540.
(1) To determine the distribution of formal patient complaints across Australia's medical workforce and (2) to identify characteristics of doctors at high risk of incurring recurrent complaints.
We assembled a national sample of all 18 907 formal patient complaints filed against doctors with health service ombudsmen (‘Commissions’) in Australia over an 11-year period. We analysed the distribution of complaints among practicing doctors. We then used recurrent-event survival analysis to identify characteristics of doctors at high risk of recurrent complaints, and to estimate each individual doctor's risk of incurring future complaints.
The distribution of complaints among doctors was highly skewed: 3% of Australia's medical workforce accounted for 49% of complaints and 1% accounted for a quarter of complaints. Short-term risks of recurrence varied significantly among doctors: there was a strong dose-response relationship with number of previous complaints and significant differences by doctor specialty and sex. At the practitioner level, risks varied widely, from doctors with <10% risk of further complaints within 2 years to doctors with >80% risk.
A small group of doctors accounts for half of all patient complaints lodged with Australian Commissions. It is feasible to predict which doctors are at high risk of incurring more complaints in the near future. Widespread use of this approach to identify high-risk doctors and target quality improvement efforts coupled with effective interventions, could help reduce adverse events and patient dissatisfaction in health systems.
PMCID: PMC3711360  PMID: 23576774
Health services research; Patient satisfaction; Quality improvement; Health policy
10.  ironXS: high-school screening for hereditary haemochromatosis is acceptable and feasible 
As the results of the Human Genome Project are realised, screening for genetic mutations that predispose to preventable disease is becoming increasingly possible. How and where such screening should best be offered are critical, unanswered questions. This study aimed to assess the acceptability and feasibility of genetic screening for preventable disease, using the model of hereditary haemochromatosis, in high-school students. Screening was offered for the HFE C282Y substitution to 17 638 students. Questionnaires were administered at the time of screening (Q1) and approximately 1 month after results were communicated (Q2). Outcomes assessed were uptake of screening, change in scores of validated anxiety, affect and health perception scales from Q1 to Q2, knowledge and iron indices in C282Y homozygous individuals. A total of 5757 (32.6%) students had screening and 28 C282Y-homozygous individuals (1 in 206) were identified, and none of the 27 individuals who had iron indices measures had significant iron overload. There was no significant change in measures of anxiety, affect or health perception in C282Y homozygous or non-homozygous individuals. Over 86% of students answered each of five knowledge questions correctly at Q1. Genetic population-based screening for a preventable disease can be offered in schools in a way that results in minimal morbidity for those identified at high risk of disease. The results of this study are not only relevant for haemochromatosis, but for other genetic markers of preventable disease such as those for cardiovascular disease and cancer.
PMCID: PMC3330225  PMID: 22234159
genetic screening; adolescent health; haemochromatosis; informed consent; high school
11.  Prevalent and Incident Bacterial Vaginosis Are Associated with Sexual and Contraceptive Behaviours in Young Australian Women 
PLoS ONE  2013;8(3):e57688.
To determine prevalence and incidence of bacterial vaginosis (BV) and risk factors in young sexually-active Australian women.
1093 women aged 16–25 years were recruited from primary-care clinics. Participants completed 3-monthly questionnaires and self-collected vaginal smears 6-monthly for 12-months. The primary endpoint was a Nugent Score = 7–10 (BV) and the secondary endpoint was a NS = 4–10 (abnormal flora [AF]). BV and AF prevalence estimates and 95% confidence intervals (95%CI) were derived, and adjusted odds ratios (AOR) calculated to explore epidemiological associations with prevalent BV and AF. Proportional-hazards regression models were used to examine factors associated with incident BV and AF.
At baseline 129 women had BV [11.8% (95%CI: 9.4–14.2)] and 188 AF (17.2%; 15.1–19.5). Prevalent BV was associated with having a recent female partner [AOR = 2.1; 1.0–4.4] and lack of tertiary-education [AOR = 1.9; 1.2–3.0]; use of an oestrogen-containing contraceptive (OCC) was associated with reduced risk [AOR = 0.6; 0.4–0.9]. Prevalent AF was associated with the same factors, and additionally with >5 male partners (MSP) in 12-months [AOR = 1.8; 1.2–2.5)], and detection of C.trachomatis or M.genitalium [AOR = 2.1; 1.0–4.5]. There were 82 cases of incident BV (9.4%;7.7–11.7/100 person-years) and 129 with incident AF (14.8%; 12.5–17.6/100 person-years). Incident BV and AF were associated with a new MSP [adjusted rate ratio (ARR) = 1.5; 1.1–2.2 and ARR = 1.5; 1.1–2.0], respectively. OCC-use was associated with reduced risk of incident AF [ARR = 0.7; 0.5–1.0].
This paper presents BV and AF prevalence and incidence estimates from a large prospective cohort of young Australian women predominantly recruited from primary-care clinics. These data support the concept that sexual activity is strongly associated with the development of BV and AF and that use of an OCC is associated with reduced risk.
PMCID: PMC3589386  PMID: 23472099
13.  Leave entitlements, time off work and the household financial impacts of quarantine compliance during an H1N1 outbreak 
BMC Infectious Diseases  2012;12:311.
The Australian state of Victoria, with 5.2 million residents, enforced home quarantine during a H1N1 pandemic in 2009. The strategy was targeted at school children. The objective of this study was to investigate the extent to which parents’ access to paid sick leave or paid carer’s leave was associated with (a) time taken off work to care for quarantined children, (b) household finances, and (c) compliance with quarantine recommendations.
We conducted an online and telephone survey of households recruited through 33 schools (85% of eligible schools), received 314 responses (27%), and analysed the subsample of 133 households in which all resident parents were employed.
In 52% of households, parents took time off work to care for quarantined children. Households in which no resident parent had access to leave appeared to be less likely to take time off work (42% vs 58%, p=0.08) although this difference had only borderline significance. Among parents who did take time off work, those in households without access to leave were more likely to lose pay (73% vs 21%, p<0.001). Of the 26 households in which a parent lost pay due to taking time off work, 42% experienced further financial consequences such as being unable to pay a bill. Access to leave did not predict compliance with quarantine recommendations.
Future pandemic plans should consider the economic costs borne by households and options for compensating quarantined families for income losses.
PMCID: PMC3533824  PMID: 23164090
14.  Chlamydia trachomatis Incidence and Re-Infection among Young Women – Behavioural and Microbiological Characteristics 
PLoS ONE  2012;7(5):e37778.
This study aimed to estimate rates of chlamydia incidence and re-infection and to investigate the dynamics of chlamydia organism load in prevalent, incident and re-infections among young Australian women.
1,116 women aged 16 to 25 years were recruited from primary care clinics in Australia. Vaginal swabs were collected at 3 to 6 month intervals for chlamydia testing. Chlamydia organism load was measured by quantitative PCR.
There were 47 incident cases of chlamydia diagnosed and 1,056.34 person years of follow up with a rate of 4.4 per 100 person years (95% CI: 3.3, 5.9). Incident infection was associated with being aged 16 to 20 years [RR = 3.7 (95%CI: 1.9, 7.1)], being employed [RR = 2.4 (95%CI: 1.1, 4.9)] and having two or more new sex partners [RR = 5.5 (95%CI: 2.6, 11.7)]. Recent antibiotic use was associated with a reduced incidence [RR:0.1 (95%CI: 0.0, 0.5)]. There were 14 re-infections with a rate of 22.3 per 100 person years (95%CI: 13.2, 37.6). The median time to re-infection was 4.6 months. Organism load was higher for prevalent than incident infections (p<0.01) and for prevalent than re-infections (p<0.01).
Chlamydia is common among young women and a high proportion of women are re-infected within a short period of time, highlighting the need for effective partner treatment and repeat testing. The difference in organism load between prevalent and incident infections suggests prevalent infection may be more important for ongoing transmission of chlamydia.
PMCID: PMC3360595  PMID: 22662220
15.  A phase i study of daily treatment with a ceramide-dominant triple lipid mixture commencing in neonates 
BMC Dermatology  2012;12:3.
Defects in skin barrier function are associated with an increase risk of eczema and atopic sensitisation. Ceramide-dominant triple lipid mixture may improve and maintain the infant skin barrier function, and if shown to be safe and feasible, may therefore offer an effective approach to reduce the incidence of eczema and subsequent atopic sensitisation. We sort to assess the safety and compliance with daily application of a ceramide-dominant triple lipid formula (EpiCeram™) commencing in the neonatal period for the prevention of eczema.
Ten infants (0-4 weeks of age) with a family history of allergic disease were recruited into an open-label, phase one trial of daily application of EpiCeram™ for six weeks. The primary outcomes were rate of compliance and adverse events. Data on development of eczema, and physiological properties of the skin (transepidermal water loss, hydration, and surface pH) were also measured.
Eighty percent (8/10) of mothers applied the study cream on 80% or more of days during the six week intervention period. Though a number of adverse events unrelated to study product were reported, there were no adverse skin reactions to the study cream.
These preliminary results support the safety and parental compliance with daily applications of a ceramide-dominant formula for the prevention of eczema, providing the necessary ground work for a randomised clinical trial to evaluate EpiCeram™ for the prevention of eczema.
Trial registration
The study was listed at the Australian/New Zealand Clinical Trial Registry (ANZCTR): reg. no. ACTRN12609000727246.
PMCID: PMC3368745  PMID: 22471265
Eczema prevention; Eczema; Skin barrier function; Asthma; Atopy
16.  HFE C282Y homozygotes with serum ferritin concentrations below 1000 μg/L are at low risk of hemochromatosis 
Hepatology (Baltimore, Md.)  2010;52(3):925-933.
HFE-associated hereditary hemochromatosis (HH) is a genetic predisposition to iron overload and subsequent signs and symptoms of disease potentially affecting around 80,000 in Australia and almost one million people in the USA. Most clinical cases are homozygous for the C282Y mutation in the HFE gene, with serum ferritin (SF) concentration >1000 μg/L the strongest predictor of cirrhosis. The optimal treatment regimen for those with SF concentrations above the normal range but <1000 μg/L is unknown. We assessed HFE mutations in a prospective cohort of 31,192 participants of northern European descent, aged 40–69 years. An HFE-stratified random sample of 1438 participants including all C282Y homozygotes with iron studies 12 years apart were examined by physicians blinded to HFE genotype. All previously undiagnosed C282Y homozygotes (35 male, 67 female) and all HFE wild-types (131 male, 160 female) with baseline and follow-up SF concentrations <1000 μg/L were assessed for HH-associated signs and symptoms including abnormal second/third metacarpophalangeal joints (MCP 2/3), raised liver enzymes, hepatomegaly, and self-reported liver disease, fatigue, diabetes mellitus, and use of arthritis medication. The prevalence of HH-associated signs and symptoms was similar for C282Y homozygotes and HFE wild-types for both normal and moderately elevated SF concentrations. The maximum prevalence difference between HFE genotype groups with moderately elevated SF was 11% (MCP 2/3 95% CI (−6%, 29%), p=0.22) and for normal SF was 6% (arthritis medicine use, 95% CI (−3, 16), p=0.11).
Previously undiagnosed C282Y homozygotes with SF concentrations that remain below 1000 μg/L are at low risk of developing HH-associated signs and symptoms at an age when disease would be expected to have developed. These observations have implications for the management of C282Y homozygotes.
PMCID: PMC2932765  PMID: 20583211
hemochromatosis; iron overload; C282Y homozygotes; serum ferritin
17.  Are Australian immigrants at a risk of being physically inactive? 
We examined whether physical activity risk differed between migrant sub-groups and the Australian-born population.
Data were drawn from the Australian National Health Survey (2001) and each resident's country of birth was classified into one of 13 regions. Data were gathered on each resident's physical activity level in the fortnight preceding the survey. Multivariable logistic regression, adjusted for potential confounders examined the risk of physical inactivity of participants from each of the 13 regions compared to the Australian-born population.
There was a greater prevalence of physical inactivity for female immigrants from most regions compared to male immigrants from a like region. Immigrants from South East Asia (OR 2.04% 95% CI 1.63, 2.56), Other Asia (OR 1.53 95% CI 1.10, 2.13), Other Oceania (1.81 95% CI 1.11, 2.95), the Middle East (OR 1.42 95% CI 0.97, 2.06 [note: border line significance]) and Southern & Eastern Europe are at a significantly higher risk of being physically inactive compared to those born in Australian. In contrast, immigrants from New Zealand (OR 0.77 95% CI 0.62, 0.94), the UK & Ireland (OR 0.82 95% CI 0.73, 0.92), and other Africa (OR 0.69 95% CI 0.51, 0.94) are at a significantly lower risk of being physically inactive compared to the Australian born population.
Future research identifying potential barriers and facilitators to participation in physical activity will inform culturally sensitive physical activity programs that aim to encourage members of specific regional ethnic sub-groups to undertake physical activity.
PMCID: PMC3125240  PMID: 21627847
19.  Maximising retention in a longitudinal study of genital Chlamydia trachomatis among young women in Australia 
BMC Public Health  2011;11:156.
Cohort studies are an important study design however they are difficult to implement, often suffer from poor retention, low participation and bias. The aims of this paper are to describe the methods used to recruit and retain young women in a longitudinal study and to explore factors associated with loss to follow up.
The Chlamydia Incidence and Re-infection Rates Study (CIRIS) was a longitudinal study of Australian women aged 16 to 25 years recruited from primary health care clinics. They were followed up via the post at three-monthly intervals and required to return questionnaires and self collected vaginal swabs for chlamydia testing. The protocol was designed to maximise retention in the study and included using recruiting staff independent of the clinic staff, recruiting in private, regular communication with study staff, making the follow up as straightforward as possible and providing incentives and small gifts to engender good will.
The study recruited 66% of eligible women. Despite the nature of the study (sexual health) and the mobility of the women (35% moved address at least once), 79% of the women completed the final stage of the study after 12 months. Loss to follow up bias was associated with lower education level [adjusted hazard ratio (AHR): 0.7 (95% Confidence Interval (CI): 0.5, 1.0)], recruitment from a sexual health centre as opposed to a general practice clinic [AHR: 1.6 (95% CI: 1.0, 2.7)] and previously testing positive for chlamydia [AHR: 0.8 (95% CI: 0.5, 1.0)]. No other factors such as age, numbers of sexual partners were associated with loss to follow up.
The methods used were considered effective for recruiting and retaining women in the study. Further research is needed to improve participation from less well-educated women.
PMCID: PMC3061916  PMID: 21385471
20.  'The difference in determinants of Chlamydia trachomatis and Mycoplasma genitalium in a sample of young Australian women.' 
Differences in the determinants of Chlamydia trachomatis ('chlamydia') and Mycoplasma genitalium (MG) genital infection in women are not well understood.
A cohort study of 16 to 25 year old Australian women recruited from primary health care clinics, aimed to determine chlamydia and MG prevalence and incidence. Vaginal swabs collected at recruitment were used to measure chlamydia and MG prevalence, organism-load and chlamydia-serovar a cross-sectional analysis undertaken on the baseline results is presented here.
Of 1116 participants, chlamydia prevalence was 4.9% (95% CI: 2.9, 7.0) (n = 55) and MG prevalence was 2.4% (95% CI: 1.5, 3.3) (n = 27). Differences in the determinants were found - chlamydia not MG, was associated with younger age [AOR:0.9 (95% CI: 0.8, 1.0)] and recent antibiotic use [AOR:0.4 (95% CI: 0.2, 1.0)], and MG not chlamydia was associated with symptoms [AOR:2.1 (95% CI: 1.1, 4.0)]. Having two or more partners in last 12 months was more strongly associated with chlamydia [AOR:6.4 (95% CI: 3.6, 11.3)] than MG [AOR:2.2 (95% CI: 1.0, 4.6)] but unprotected sex with three or more partners was less strongly associated with chlamydia [AOR:3.1 (95%CI: 1.0, 9.5)] than MG [AOR:16.6 (95%CI: 2.0, 138.0)]. Median organism load for MG was 100 times lower (5.7 × 104/swab) than chlamydia (5.6 × 106/swab) (p < 0.01) and not associated with age or symptoms for chlamydia or MG.
These results demonstrate significant chlamydia and MG prevalence in Australian women, and suggest that the differences in strengths of association between numbers of sexual partners and unprotected sex and chlamydia and MG might be due to differences in the transmission dynamics between these infections.
PMCID: PMC3038161  PMID: 21284887
21.  Comparing the frequency of common genetic variants and haplotypes between carriers and non-carriers of BRCA1 and BRCA2 deleterious mutations in Australian women diagnosed with breast cancer before 40 years of age 
BMC Cancer  2010;10:466.
BRCA1 and BRCA2 mutations are found in a proportion of families with multiple early-onset breast cancers. There are a large number of different deleterious mutations in both genes, none of which would be detectable using standard genetic association studies. Single common variants and haplotypes of common variants may capture groups of deleterious mutations since some low prevalence haplotypes of common variants occur more frequently among chromosomes that carry rare, deleterious mutations than chromosomes that do not.
DNA sequence data for BRCA1 and BRCA2 was obtained from 571 participants from the Australian Breast Cancer Family Study. Genetic variants were classified as either deleterious mutations or common genetic variants. Variants tagging common polymorphisms were selected and haplotypes resolved using Haploview. Their frequency was compared to those with and without deleterious mutations using a permutation test.
A common genetic variant in BRCA1 (3232A > G) was found to be over-represented in deleterious mutation carriers (p = 0.05), whereas a common genetic variant in BRCA2 (1342A > C) occurred less frequently in deleterious mutation carriers (p = 0.04). All four of the common BRCA1 variants used to form haplotypes occurred more frequently in the deleterious mutation carriers when compared to the non-carriers, but there was no evidence of a difference in the distributions between the two groups (p = 0.34). In BRCA2, all four common variants were found to occur less frequently in the deleterious mutation carriers when compared to non-carriers, but the evidence for difference in the distribution between the two groups was weak (p = 0.16). Several less common haplotypes of common BRCA1 variants were found to be over-represented among deleterious mutation carriers but there was no evidence for this at the population level. In BRCA2, only the most common haplotype was found to occur more frequently in deleterious mutation carriers, with again no evidence at the population level.
We observed differences in the frequency of common genetic variants of the BRCA1 and BRCA2 and their haplotypes between early-onset breast cancer cases who did and did not carry deleterious mutations in these genes. Although our data provide only weak evidence for a difference in frequencies at the population level, the number of deleterious mutation carriers was low and the results may yet be substantiated in a larger study using pooled data.
PMCID: PMC2940805  PMID: 20807450
22.  Incentive payments to general practitioners aimed at increasing opportunistic testing of young women for chlamydia: a pilot cluster randomised controlled trial 
BMC Public Health  2010;10:70.
Financial incentives have been used for many years internationally to improve quality of care in general practice. The aim of this pilot study was to determine if offering general practitioners (GP) a small incentive payment per test would increase chlamydia testing in women aged 16 to 24 years, attending general practice.
General practice clinics (n = 12) across Victoria, Australia, were cluster randomized to receive either a $AUD5 payment per chlamydia test or no payment for testing 16 to 24 year old women for chlamydia. Data were collected on the number of chlamydia tests and patient consultations undertaken by each GP over two time periods: 12 month pre-trial and 6 month trial period. The impact of the intervention was assessed using a mixed effects logistic regression model, accommodating for clustering at GP level.
Testing increased from 6.2% (95% CI: 4.2, 8.4) to 8.8% (95% CI: 4.8, 13.0) (p = 0.1) in the control group and from 11.5% (95% CI: 4.6, 18.5) to 13.4% (95% CI: 9.5, 17.5) (p = 0.4) in the intervention group. Overall, the intervention did not result in a significant increase in chlamydia testing in general practice. The odds ratio for an increase in testing in the intervention group compared to the control group was 0.9 (95% CI: 0.6, 1.2). Major barriers to increased chlamydia testing reported by GPs included a lack of time, difficulty in remembering to offer testing and a lack of patient awareness around testing.
A small financial incentive alone did not increase chlamydia testing among young women attending general practice. It is possible small incentive payments in conjunction with reminder and feedback systems may be effective, as may higher financial incentive payments. Further research is required to determine if financial incentives can increase testing in Australian general practice, the type and level of financial scheme required and whether incentives needs to be part of a multi-faceted package.
Trial Registration
Australian New Zealand Clinical Trial Registry ACTRN12608000499381.
PMCID: PMC2841675  PMID: 20158918
23.  Relationship between Vehicle Emissions Laws and Incidence of Suicide by Motor Vehicle Exhaust Gas in Australia, 2001–06: An Ecological Analysis 
PLoS Medicine  2010;7(1):e1000210.
In an ecological study, David Studdert and colleagues show that areas of Australia with fewer vehicles pre-dating stringent carbon monoxide emission laws have lower rates of suicide due to asphyxiation by motor vehicle exhaust gas.
Globally, suicide accounts for 5.2% of deaths among persons aged 15 to 44 years and its incidence is rising. In Australia, suicide rates peaked in 1997 and have been declining since. A substantial part of that decline stems from a plunge in suicides by one particular method: asphyxiation by motor vehicle exhaust gas (MVEG). Although MVEG remains the second most common method of suicide in Australia, its incidence decreased by nearly 70% in the decade to 2006. The extent to which this phenomenon has been driven by national laws in 1986 and 1999 that lowered permissible levels of carbon monoxide (CO) emissions is unknown. The objective of this ecological study was to test the relationship by investigating whether areas of Australia with fewer noxious vehicles per capita experienced lower rates of MVEG suicide.
Methods and Findings
We merged data on MVEG suicides in Australia (2001–06) with data on the number and age of vehicles in the national fleet, as well as socio-demographic data from the national census. Poisson regression was used to analyse the relationship between the incidence of suicide within two levels of geographical area—postcodes and statistical subdivisions (SSDs)—and the population density of pre-1986 and pre-1999 passenger vehicles in those areas. (There was a mean population of 8,302 persons per postcode in the study dataset and 87,413 persons per SSD.) The annual incidence of MVEG suicides nationwide decreased by 57% (from 2.6 per 100,000 in 2001 to 1.1 in 2006) during the study period; the population density of pre-1986 and pre-1999 vehicles decreased by 55% (from 14.2 per 100 persons in 2001 to 6.4 in 2006) and 26% (from 44.5 per 100 persons in 2001 to 32.9 in 2006), respectively. Area-level regression analysis showed that the suicide rates were significantly and positively correlated with the presence of older vehicles. A percentage point decrease in the population density of pre-1986 vehicles was associated with a 6% decrease (rate ratio [RR] = 1.06; 95% confidence interval [CI] 1.05–1.08) in the incidence of MVEG suicide within postcode areas; a percentage point decrease in the population density of pre-1999 vehicles was associated with a 3% decrease (RR = 1.03; 95% CI 1.02–1.04) in the incidence of MVEG suicide.
Areas of Australia with fewer vehicles predating stringent CO emission laws experience lower rates of MVEG suicide. Although those emission laws were introduced primarily for environmental reasons, countries that lack them may miss the benefits of a serendipitous suicide prevention strategy.
Please see later in the article for the Editors' Summary
Editors' Summary
Suicide (self-inflicted death) is a major, preventable public-health problem. About 1 million people die each year from suicide and about 20 times as many people attempt suicide. Globally, suicide rates have increased by nearly a half over the past 45 years and suicide is now among the three leading causes of death in people aged 15–44 years. Within this age group, 1 in 20 deaths is a suicide. Most people who commit suicide have a mental illness, usually depression or substance abuse, but suicide can also be triggered by a stressful event such as losing a partner. Often warning signs are present—a person who talks about killing themselves must always be taken seriously. Adequate prevention and treatment of mental illness and interventions that teach young people coping skills and improve their self-esteem have shown promise in reducing suicide rates, as have strategies (for example, restrictions on the sale of pain killers) that reduce access to common methods of suicide.
Why Was This Study Done?
In Australia, the suicide rate has been declining since 1997 when a record 2,722 suicides occurred. Fewer suicides by asphyxiation (oxygen deprivation) by motor vehicle gas exhaust (MVEG) account for much of this decline. MVEG contains carbon monoxide, a toxic gas that blocks oxygen transport around the body. Although MVEG suicide is still the second most common means of suicide in Australia, its incidence has dropped by two-thirds since 1997 but why? One possibility is that national laws passed in 1986 and 1999 that lowered the permissible level of carbon monoxide in vehicle exhaust for environmental reasons have driven the decline in MVEG suicides. Evidence from other countries suggests that this might be the case but no-one has directly investigated the relationship between MVEG suicide and the use of vehicles with reduced carbon monoxide emissions. In this ecological study (a study in which the effect of an intervention is studied on groups of people rather than on individuals), the researchers ask whether the number of pre-1986 and pre-1999 vehicles within particular geographic areas in Australia is correlated with the rates of MVEG suicide in those areas between 2001 and 2006.
What Did the Researchers Do and Find?
The researchers obtained data on MVEG suicides from the Australian National Coroners Information System and data on the number and age of vehicles on the road from the Australian Bureau of Statistics. MVEG suicides dropped from 498 in 2001 to 231 in 2006, they report, and 28% of passenger vehicles registered in Australia were made before 1986 in 2001 but only 12% in 2006; the percentage of registered vehicles made before 1999 fell from 89% to 60% over the same period. The researchers then used a statistical technique called Poisson regression to analyze the relationship within postcode areas between the incidence of MVEG suicide and the presence of pre-1986 and pre-1999 vehicles. This analysis showed that in areas where older vehicles were more numerous there were more MVEG suicides (a positive correlation). Specifically, the researchers calculate that if the proportion of pre-1986 vehicles on the road in Australia had stayed at 2001 levels throughout their study period, 621 extra MVEG suicides would have occurred in the country over that time.
What Do These Findings Mean?
These findings show that in areas of Australia that had fewer vehicles on the road predating stringent vehicle emission laws, there were lower rates of MVEG suicide between 2001 and 2006. Unfortunately, this study cannot provide any information on the actual age of vehicles used in MVEG suicides or on the relationship between vehicle age and attempted MVEG suicides. It also cannot reveal whether those areas that had the sharpest decreases in the density of older vehicles had the sharpest decreases in suicide rates because very few suicides occurred in most postcodes during the study. Most importantly, the design of this study means that the researchers cannot discount the possibility that the changes in Australia's emission laws have steered people towards other methods of taking their own lives. Nevertheless, the findings of this study suggest that the introduction of stringent vehicle emission laws for environmental reasons might, serendipitously, be a worthwhile long-term suicide prevention strategy in countries where MVEG suicide is common.
Additional Information
Please access these Web sites via the online version of this summary at
Another PLoS Medicine research article, by Shu-Sen Chang and colleagues, investigates the evolution of the epidemic of charcoal-burning suicide in Taiwan
The US National Institute of Mental Health provides information on suicide and suicide prevention
The UK National Health Service Choices Web site has detailed information about suicide and its prevention
The World Health Organization provides information on the global burden of suicide and on suicide prevention (in several languages)
MedlinePlus provides links to further resources about suicide (in English and Spanish)
Suicide Prevention Australia is a nonprofit, nongovernmental organization working as a public-health advocate in suicide prevention
The Australian Institute of Health and Welfare has recently published a review of suicide statistics in Australia
The National Coroners Information System is a database contains information on every death reported to an Australian coroner since July 2000 (January 2001 for Queensland)
PMCID: PMC2796388  PMID: 20052278
24.  Predictors of mammographic density: insights gained from a novel regression analysis of a twin study 
Understanding which factors influence mammographically dense and non-dense areas is important because percent mammographic density (PMD) adjusted for age is a strong, continuously distributed risk factor for breast cancer, especially when adjusted for weight or body mass index. Using computer-assisted methods, we measured mammographically dense areas for 571 monozygotic and 380 dizygotic Australian and North American twin pairs aged 40 to 70 years. We used a novel regression modelling approach in which each twin’s measure of dense and non-dense area was regressed against one or both of the twin’s and co-twin’s covariates. The nature of changes to regression estimates with the inclusion of the twin and/or co-twin’s covariates can be evaluated for consistency with causal and/or other models. By causal we mean that if it were possible to vary a covariate experimentally then the expected value of the outcome measure would change. After adjusting for the individual’s weight, the co-twin associations with weight were attenuated, consistent with a causal effect of weight on mammographic measures which in log cm2/kg was three times stronger for non-dense than dense area. After adjusting for weight, later age at menarche and greater height were associated with greater dense and lesser non-dense areas in a manner inconsistent with causality. The associations of dense and non-dense areas with parity are consistent with a causal effect and/or within-person confounding. The associations between mammographic density measures and height are consistent with shared early life environmental factors that predispose to both height and PMD and possibly breast cancer risk.
PMCID: PMC2677104  PMID: 19064564
25.  Problems assessing uptake of Huntington disease predictive testing and a proposed solution 
The uptake of predictive testing for Huntington disease informs our understanding of decision making by those at risk and assists with planning for service provision. Uptake figures have been reported from several centers based on the total number of people who have undertaken predictive testing as a percentage of those estimated to be at 50% risk in the region. This method produced a figure of 35% from our own service, much higher than observation of the local pedigrees indicated, and higher than other published reports. We have identified some errors in the commonly used formula. The major errors are the use of the cumulative total of those who have had testing with a static denominator of those at 50% risk, and the failure to exclude from the at-risk group those who are too young and therefore ineligible to test.
We report data from the Huntington Disease Register of Victoria and estimate the prevalence to be 8 per 100 000 in 1999. Additional data on individuals at risk were collated. We found that for every diagnosed person there were 4.2 individuals at 50% risk, a lower ratio than one to five hypothesized in the literature. We examined these ratios in the context of uptake.Significantly, we provide a solution to the calculation of uptake with a formula that factors in a dynamic denominator and corrects for the number of years testing has been offered. Using this formula, we calculated an uptake of 13.0–15.4% for the state of Victoria, Australia. This formula can be used to compare uptake across different centers.
PMCID: PMC2985957  PMID: 18665196
Huntington disease; uptake; prevalence; predictive testing

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